Date of Award

January 2016

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Serena Spudich

Abstract

The central nervous system (CNS) may serve as a reservoir for HIV, associated with the emergence or persistence of viral strains distinct from the periphery. This can lead to incomplete treatment of the CNS and neurologic symptoms, and is an obstacle in the pursuit of an HIV cure. Deep sequencing (DS) can detect low frequency variants that comprise <20% of the viral population. We used Roche 454 and Illumina MiSeq technologies to perform a longitudinal DS analysis of the HIV envelope (env), reverse transcriptase (RT), and protease (PR) genes to compare variants present in the cerebrospinal fluid (CSF) and plasma compartments in subjects recruited during primary infection. The frequency of resistance mutations, defined according to the Stanford HIV database, was analyzed between compartments. High frequency drug resistance mutations were concordant in the compartments although each subject had minority variants identified in either compartment. Geno2pheno analysis to predict coreceptor tropism revealed majority CCR5-using variants in all specimens from both compartments. Longitudinal DS can provide a detailed view of HIV evolution in the CSF compartment with respect to plasma over time. The presence of distinct compartmentalized variants at the same time point suggests that even in early infection there may be autonomous sources of HIV in the CNS. However, low frequency mutations did not appear to affect subjects’ clinical response to antiretroviral therapy (ART).

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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